The first member of the vancomycin family of peptide antibiotics was isolated in 1956, and the progenitor of the family, vancomycin, has been in clinical use for more than twenty-three years as an "antibiotic of last resort." Over the intervening years it has been discovered that there are no naturally occuring strains of bacteria which are immune to the bacterocidal effects of vancomycin and the more than thirty vancomycin variants which have been isolated and identified over the last two decades. The first objective in this proposal is to develop an efficient approach to the synthesis of the principal vancomycin and ristocetin subunits, vancomycinic acid, actinoidinic acid and ristomycinic acid. Through this exercise we intend to confirm the stereochemical assignments of both vancomycin and ristocetin. We then will pursue a laboratory synthesis of vancomycin and the related congeners orienticin C, ristocetin and aridicin A. In conjunction with the execution of these objectives, we will develop new methods for the asymmetric synthesis of complex amino acids and cyclic peptides. In addition, we propose to develop new methodology for the oxidative macrocyclization of phenol-containing peptides to form macrocyclic diphenylethers and biphenyls, critical constituents of the vancomycin skeleton. The successful development of this methodology will enable us to pursue a biogenetically modeled synthesis of virtually any member of the vancomycin family. Finally, the full stereochemical assignments of all members of this family of antibodies rests on NMR spectroscopy, and as such must be considered as tentative. During the course of this project we intend to confirm (correct) the absolute stereochemical assignment of the principal members of this family by total synthesis.